Alzheimer's disease (AD) is a neurodegenerative disorder that is the most common cause of dementia among elderly persons. It is characterized by progressive memory loss, synaptic dysfunction and accumulation of amyloid β-peptides (Aβ). It is caused in part by increased levels of amyloid-β-peptide 1-42 (Aβ42). Approved drugs to treat AD include cholinesterase inhibitors such as Cognex® (tacrine), Aricept® (donepezil), Exelon® (rivastigmine) and Razdyne® (galantamine); and the N-methyl d-aspartate receptor antagonist Namenda® (memantine). However, several of these medications suffer from limited efficacy and produce untoward side effects.
Phosphodiesterase 5 (PDE5) inhibitors are widely used as therapeutics for erectile dysfunction and pulmonary hypertension. These inhibitors are believed to increase cGMP levels, which enhances phosphorylation of the transcription factor and memory-affecting molecule cAMP-responsive element binding (CREB) through activation of cGMP-dependent-protein kinases.
Cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP), nucleotide biological second messengers, regulate various biological processes, such as blood flow regulation, cardiac muscle contraction, cell differentiation, neural transmission, glandular secretion, and gene expression. Intracellular receptors for these molecules include cyclic nucleotide phosphodiesterases (PDEs), cyclic nucleotide dependent protein kinases (PGK), and cyclic nucleotide-gated channels. PDEs are a large family of proteins that catalyze the hydrolysis of 3′,5′-cyclic nucleotides to the corresponding 5′ monophosphates. There are eleven related, but biochemically distinct, human PDE gene groups. Some PDEs are specific for hydrolysis of cAMP (such as PDE4, PDE7, and PDE8), and some are cGMP specific (such as PDE5, PDE6, and PDE5), while some PDEs have mixed specificity (such as PDE1, PDE2, PDE3, PDE10, and PDE11).
Representative PDE 5 inhibitors are cyclic guanosine 3′,5′-monophosphate type five cGMP PDE inhibitors, also known as PDE-5 inhibitors, which include, for example, sildenafil, tadalafil, zaprinast, and vardenafil. PDE5 inhibitors increase cGMP levels by inhibiting the degradative action of PDE5 on cGMP. Current PDE5 inhibitors suffer from drawbacks such as limited selectivity over other PDE sub-types. There remains a need for structurally novel PDE5 inhibitors.